Force production by disassembling microtubules

Grishchuk, Ekaterina L.; Molodtsov, Maxim I.; Ataullakhanov, Fazly I.; McIntosh, J. Richard

doi:10.1038/nature04132

Cited by 263 publications

(258 citation statements)

References 30 publications

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“…Indeed, microtubule depolymerization can generate a force 10 times greater than that of a microtubule motor protein. 123 The force of microtubule plus-end depolymerization has a crucial role in generating the tension that pulls a chromatid from its sister. [124][125][126] In fact, in fission yeast, minus end-directed motor proteins are entirely dispensable for poleward motion of chromosomes -the force generated by microtubule depolymerization is sufficient.…”

Section: Surviving With Surplus: Managing Supernumerary Centrosomes Bmentioning

confidence: 99%

Let's huddle to prevent a muddle: centrosome declustering as an attractive anticancer strategy

2012

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Nearly a century ago, cell biologists postulated that the chromosomal aberrations blighting cancer cells might be caused by a mysterious organelle-the centrosome-that had only just been discovered. For years, however, this enigmatic structure was neglected in oncologic investigations and has only recently reemerged as a key suspect in tumorigenesis. A majority of cancer cells, unlike healthy cells, possess an amplified centrosome complement, which they manage to coalesce neatly at two spindle poles during mitosis. This clustering mechanism permits the cell to form a pseudo-bipolar mitotic spindle for segregation of sister chromatids. On rare occasions this mechanism fails, resulting in declustered centrosomes and the assembly of a multipolar spindle. Spindle multipolarity consigns the cell to an almost certain fate of mitotic arrest or death. The catastrophic nature of multipolarity has attracted efforts to develop drugs that can induce declustering in cancer cells. Such chemotherapeutics would theoretically spare healthy cells, whose normal centrosome complement should preclude multipolar spindle formation. In search of the 'Holy Grail' of nontoxic, cancer cell-selective, and superiorly efficacious chemotherapy, research is underway to elucidate the underpinnings of centrosome clustering mechanisms. Here, we detail the progress made towards that end, highlighting seminal work and suggesting directions for future research, aimed at demystifying this riddling cellular tactic and exploiting it for chemotherapeutic purposes. We also propose a model to highlight the integral role of microtubule dynamicity and the delicate balance of forces on which cancer cells rely for effective centrosome clustering. Finally, we provide insights regarding how perturbation of this balance may pave an inroad for inducing lethal centrosome dispersal and death selectively in cancer cells.

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Section: Surviving With Surplus: Managing Supernumerary Centrosomes Bmentioning

confidence: 99%

Let's huddle to prevent a muddle: centrosome declustering as an attractive anticancer strategy

2012

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“…Our findings help establish the benchmark parameters of the Dam1 coupler and elucidate the mechanism of its functions. Dam1 | microtubule | kinetochore D uring mitotic chromosome segregation, sister chromatids are tightly attached to spindle MTs, and their migration is powered by MT depolymerization as well as specific motor proteins (1). The kinetochore (k), a mega-protein complex assembled on the centromere of each chromosome, mediates the association between the chromosome and the kMTs, and is responsible for generating the pulling forces for chromosome motions (2).…”

mentioning

confidence: 99%

A non-ring-like form of the Dam1 complex modulates microtubule dynamics in fission yeast

Gao

Courthéoux

Gachet

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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The Dam1 complex is a kinetochore component that couples chromosomes to the dynamic ends of kinetochore microtubules (kMTs). Work in the budding yeast Saccharomyces cerevisiae has shown that the Dam1 complex forms a 16-unit ring encircling and tracking the tip of a MT in vitro, consistent with its cellular function as a coupler. Dam1 also forms smaller, nonring patches in vitro that track the dynamic ends of MTs. However, the identity of Dam1’s functional form in vivo remains unknown. Here we report a comprehensive in vivo characterization of Dam1 in the fission yeast Schizosaccharomyces pombe . In addition to their dense localizations on kinetochores and spindle MTs during mitosis, we identify that Dam1 is also localized onto cytoplasmic MTs as discrete spots in interphase, providing the unique opportunity to analyze Dam1 oligomers at the single-particle resolution in live cells. Such analysis shows that each oligomer contains one to five copies of Dam1, and is able to “switch-rail” while moving along MTs, precluding the possibility of a 16-unit encircling structure. Dam1 patches track the plus ends of the shortening, but not the elongating, MTs and retard MT depolymerization. Together with Mal3, the EB1-like MT-interacting protein, cytoplasmic Dam1 plays an important role in maintaining proper cell shape. In mitosis, kinetochore-associated Dam1 appears to facilitate kMT depolymerization. Together, our findings suggest that patches, instead of rings, are the physiologically functional forms of Dam1 in pombe. Our findings help establish the benchmark parameters of the Dam1 coupler and elucidate the mechanism of its functions.

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“…Accordingly, it was determined that the maximal force generated was ~46 pN, which might correspond to the bending of 1 or 2 protofilaments. This is about 10 times the force developed by kinesin molecules [137] and it is expected that at kinetochores, with a proper coupler, all protofilaments would act in concert, increasing the force generated by a depolymerizing microtubule to at least 30-65 pN [136]. In agreement, the force produced by this system was shown to be dependent on the curvature of protofilaments [138].…”

Section: Force Generation By Microtubule Depolymerization From Plus-endsmentioning

confidence: 61%

“…In 2005, McIntosh and co-workers provided theoretical and experimental evidence in support of the conformational-wave model [135,136]. By conjugating streptavidin coated glass microbeads to biotinylated microtubules they observed that upon depolymerization, microtubules exert a brief pull on the beads before being released.…”

Section: Force Generation By Microtubule Depolymerization From Plus-endsmentioning

confidence: 99%

The perpetual movements of anaphase

Maiato

Lince-Faria

2010

Cell. Mol. Life Sci.

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One of the most extraordinary events in the lifetime of a cell is the coordinated separation of sister chromatids during cell division. This is truly the essence of the entire mitotic process and the reason for the most profound morphological changes in cytoskeleton and nuclear organization that a cell may ever experience. It all occurs within a very short time window known as "anaphase", as if the cell had spent the rest of its existence getting ready for this moment in an ultimate act of survival. And there is a good reason for this: no space for mistakes. Problems in the distribution of chromosomes during cell division have been correlated with aneuploidy, a common feature observed in cancers and several birth defects, and the main cause of spontaneous abortion in humans. In this paper we critically review the mechanisms of anaphase chromosome motion that resisted the scrutiny of more than one hundred years of research as part of a tribute to the pioneering work of Miguel Mota.

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Force production by disassembling microtubules

Cited by 263 publications

References 30 publications

Let's huddle to prevent a muddle: centrosome declustering as an attractive anticancer strategy

Let's huddle to prevent a muddle: centrosome declustering as an attractive anticancer strategy

A non-ring-like form of the Dam1 complex modulates microtubule dynamics in fission yeast

The perpetual movements of anaphase

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